Muscle weakness sliding into place

A zebrafish embryo (top) with weakened muscles.

Our ability to walk, run or breathe is dependent on the electric slide of actin, myosin and other proteins within our muscles. Much of our understanding of this synchronized dance comes from studying mice and human patients with genetic mutations that cause muscle weakness. Now, Alan Beggs, director of the Manton Center for Orphan Disease Research at Children’s, has taken a step in a different direction: zebrafish.

By modeling muscle diseases in these fast-growing fish, Beggs hopes to gain quicker insight into how our muscles move and develop therapies, particularly for a group of rare muscle-weakening disorders known as congenital myopathies.

“In the course of just a few days, you can watch an entire zebrafish develop from an egg to a free swimming fish, complete with all the muscles necessary for movement,” says Beggs. “In mice, or other organisms, similar experiments would take months, or even years.”

Alan Beggs, PhD and his zebrafish team: undergraduate student Stacey Gundry, and postdoctoral fellow Vandana Gupta, PhD.

Collaborating with the lab of Wayne Lencer, chief of the Division of Gastroenterology, Beggs’s postdoctoral fellow Vandana Gupta bred thousands of genetically defective fish and watched them grow from the embryonic stage as their muscles developed. She found several with muscle defects similar to those seen in patients with congenital myopathies, such as multiminicore disease and nemaline myopathy.

Now, Gupta is studying these fish to discover the altered genes and determine how they cause muscle weakness. In the future, she hopes to use these fish in large numbers to screen for new drugs to combat these diseases.

With postdoctoral fellow Genri Kawahara, in the lab of Lou Kunkel, director of the Program in Genomics, Gupta is also screening for drugs effective against muscular dystrophy, a more common form of muscle weakness.

“Because zebrafish develop so quickly, we can easily screen thousands of drugs for their effect on muscle development in just a short amount of time,” says Beggs. “That’s the real power of the zebrafish.”

Read more about Begg’s work on congenital myopathies and watch a YouTube video about zebrafish and how they’re being used in stem cell biology.